21-bromopregnenes



I that of the naturally occurring adrenal hormones, 50

Patented Dec. .27, i949 in A p v z 49z 191 UNITED STATES PATENT OFFICE 21 -BROMOPREGNENES Lewis H. Sarett, Princeton, N. assignor a Merck & 00., Inc., Railway, N. 1., a corporation of New Jersey No Drawing. Original application July 14, 1945, I Serial No. 605,194. Divided andfliis application February-23, 1946, Serial No. 649,763

1 3 Claims. (01. 260-3974) 2 This invention is concerned generally withformulae the former configuration is shown by novel chemical compounds of the cyclopentanodiwriting the (2-17 substituent (hydroxyl) to the methylpolyhydrophenanthrene series and to procright of the -17 carbon side chain, thus esses of preparing same; more particularly it re- CHOH' lates to novel compounds useful as intermediates in the synthesis of the adrenal cortical hormone HOE A4,5-3,11,20 triketo 17(5) 21 dihydroxy pregnene. This application is a divisional of copending application Serial No. 605,194, filed July 14, 1945, now abandoned.

in the latter case above the side chain, thus This hormone is known to occur naturally in H CH=CH the adrenal cortex; it has the structural formula: I

zlcmon H 19 3. The stereochemical relationship of rings A 0 and B is indicated in the formulae by a solid line I/ representing the valence bond in the cis configu- 011 013 D 16CH2 ration 5 g G g 15 H In accordance with the present invention it is /1\| g 20 now found this hormone can be synthesized by H202 C10 8C reactions indicated as follows:

A B 0=J:3 5L W lli: E

\ \g/ H-com H-COzH H H1 CH1 CH3 (Standard numbering of C-positions) O O s This formula, for purposes of convenience, is acylating \A hereinafter reproduced below in the abbreviated CH3 agent CH3 form:

=0 HO no OH; OH H H I II I I acyl-lialide- CH. liaise CH: $1 oil-(JON: CH-COX 0 4o on, CH;

In the following description of the invention, MN; the stereochemical relationships of substituents 0113 CH; are indicated by the following conventions:

1. A substituent at the 0-3 position which is trans to the 0-10 methyl group is parenthetically designated (an). R0 I R0 2. A substituent at the 0-17 position, the stereo- H chemical configuration of which is identical with IV In is parenthetically designated (a); the epimeric configuration is designated (a) In the structural a l o 1 coin A300,

I o I OH o\ OH: on

H E vn XII x! E Y OH OH O OH 0508 =CH1 CH: o I I H Nh OH 20 on. CHI CH 0 HI- ably! OH: n no no w xm XIV gcylatltng an no HONO I CHI Unix, .8

HOB 6H on v CH CH: QCH:

O 0\ o\ cm CH, CH:

hum agent H o XVI xv cn-cmx' H CH0R" VIII C CH: OH: O\ 0\ an: o CH MOB" CH CH CH XVII O\ o\ C XVI 8' RIO CH: hydrolysis II He C R o i n! CH-CHIOH a CH CH: H 1x R'OHor o\ luho CH, 0110 CH OH I an (011 CEO XIX mo [01115103 x on ygz CH 604 com 0 flon 0\ H0 HO OH: OH H H [oxidation cn cm0 03-01mm B CH, CH:

0 O H H h dnflvn J x I on an on XXI xx 1) o O I m acy afl z mnt II a OHaOH HOE OH-CHgO 3''" cm on on I: drew- Yam;

agent CH CH:

XXII XXIII acylating agent RII!!! RI]!!! HORIIII! RI]!!! CH1, OH CH3 OH o 0 CH: X CH:

XXV XXIV H cHzoRlllll RI]!!! H 0 R!!! H 0 RI!!! OH: OH CH3 OH on, pyridine sin; 0 0g XXVI x]! XXV l hydrolysis CH O R C H: OH

H OH H--OH OH: OH CH3! OH I 0 CH: (R)2O C111: 0 O

XXVIII XXVII 1 oxidation =0 0 OH: OH OH I CH: C|Ha 0 O I XXIX XXX 1 hydrolysis CHlOH CH1 0H In the above formulae, R, R, R", R', R"", R""', and R are acyl; X, X and X are halogen; and M is an alkali metal or an alkaline earth metal /2.

The reactions above indicated are conducted as follows:

3-hydroxy-ll-keto-bisnorcholanic acid (I) is acylated producing 3-acyloxy-ll-keto-bisnorcholanic acid (II) which is treated with an agent capable of converting an organic carboxylic acid to the corresponding acid halide, thus forming the acid halide of 3-acyloxy-1l-keto-bisnorcholanic acid (III). Upon treatment of this acid halide with an alkali metal azide or alkaline earth metal azide, the azide of 3-acyloxy-11-keto-bisnorcholanic acid (IV) is formed. Decomposition of this azide with an acidic aqueous solution pro duces 3-acyloxy-11-keto-20-aminopregnane (V). Upon treatment of this compound (V) with nitrous acid, a mixture containing predominantly A" 3 acyloxy 11 keto-pregnene (VI) and A=' -3-acyloxy-1l-keto-pregnene (VII) and a minor amount of 3-acyloxy-11-keto-20-hydroxy- 'pregnane (VIII) results. The proportion of the desired compound (VI) present in this mixture can be increased by treating the mixture with an aromatic sulfonyl halide followed by further treatment with a base to cause removal of the elements of the corresponding aromatic sulfonic acid. The mixture of these compounds (VI) and (VH) or of (VI), (VII) and (VIII), is then treated with ozone followed by decomposition of the ozonide, producing 3-acyloxy-11,1'7-diketoetiooholane (IX) and 3-acyloxy-1l-keto-l'l-formyletioch-olane (X). Compound (X) is oxidized to 3-acyloxy-1l-ketoetiocholanic acid (IX) which is separated from compound (IX) by extraction with alkali.

Compound (IX) is hydrolyzed to form 3-hydroxy 11,17 diketoetiocholane (XII) which is treated with acetylene to form 3,1'7-dihydroxy-11- keto-pregnine-ZO (XIII). This compound (XIII) is catalytically hydrogenated to produce A 3,17-dihydroxy-lI-lretopregnene (XIV) which, is acylated to form A -3-acyloxy-17-hydroxy-11- ketopregnene (XV), and this compound is halogenated to produce A -3-acyloxy-11-keto-21- halopregnene (XVI). When treated with an alkali meta-1 salt or alkaline earth metal salt of an organic acid, this com ound yields A -3,21- diacyloxy-ll-ketopregnene (XVII) which is hydrolyzed producing A -3,21-dihydroxyll-ketopregnene (XVIII). The latter product (XVIII) is partially esterifled and the mono ester (XIX) thus produced is oxidized to convert the unesterifled hydroxy group in the 3 position to a keto group, thereby yielding the ester of A -3,11-

diketo-21-acyl0Xy-pregnene (XX). This product (XX) is hydrolyzed and the A -3,11-diket0-21- hydroxypregnene (XXI) thus formed is acylated producing A -3,1l-diketo-Zl-acyloxypregnene (XXII). Hydroxylation at the unsaturation of capable of removing the elements of hydrogen bromide, thereby producing A 3,11 -diketo- 17 (p) -hydroxy-20,2l-di-acyloiwpregnene (XXVI) which on hydrolysis forms A -3,11- diketo- 17(,B),20,21-trihydroxypregnene (XXVII). Partial acylation of this compound (XXVII) gives A -3,1 l-diketo-17 (p) ,20 dihydroxy 21 acyloxypregnenc (XXVIII) which, when oxidized, yields a mixture of A*"-3,11,20-triketo-17(3)-hydroxy- 21-a-cyloxypregnene (XXIX) and A -3,11,1'7-triketo androstene (XXX). Compounds QQIIX) and (XXX) may be separated by conventional operations, for example chromatography, and compound (XXIX) hydrolyzed to pnoduce the desired adrenal hormone, A 3,11,20 triketo- 17 (fl) ,ZI-dihydroxypregnene.

This invention is concerned with compounds of the type represented by intermediate 16 above, and with processes of producing same, which intermediate is represented by the formula CHQX OH; H

in which R is acyl or hydrogen and X is halogen.

The starting material employed in the process according to this invention, a A -3--acyloxy-11- keto- 17 -hydroxypregnene, may be obtained as described in copending application Serial No. 649,762, filed February 23, 1946.

In accordance with this invention, A -3-acyloxy-i'l-hydroxy-ll-ketopregnene is halogenated in the presence of a small amount of halogenation catalyst such as pyridine and in an inert solvent medium such as chloroform, to produce the corresponding A -3-acyloxy-l1-keto-21-halopregnene. As halogenatin agents, phosphorous tribromide, phosphorous trichloride, thionyl chloride may be used. It is found that the 17 hydroxyl group is thus replaced by a halogen atom and that the unsaturated system undergoes an allylic shift, yielding a product having the structural formula:

CHzX

CH3 H in which R acyl (preferably a lower aliphatic acyl group having 6 or less carbon atoms), and X is halogen. The acyl radical in the 3 position may be converted to hydroxyl by saponification and, of course, this compound may -be esterified with an acid such as acetic, propionic, butyric, valeric;

caproic, capric, eta, be 1111c, l

8 acetic. an acid anhydride or other acylating agent. The preferred acylating agents are the lower aliphatic acid anhydrides, i. e. those of acid having 6 carbons or less, of which acetic anhydride is preferred.

The following example, which is illustrative of the practice of this invention, discloses the detailed process for the bromination of A -3(a) acetoxy-17(a) hydroxy-11-ketopregnene; it will be understood the invention is not limited to this particular procedure or to treatment of this speciflc compound or use of the indicated halogenating reagent.

Example To a solution of mg. phosphorous tribromide in .74 cc. of absolute chloroform at 60 C. is added dropwise a solution of 400 mg. of A -3 3(a) acetoxy 17(a) hydroxy 11- ketopregnene in 5.8 cc. of absolute chloroform. Two drops of pyridine were added and the mixture was permitted to stand at room temperature overnight. A solution of sodium bicarbonate was added and the mixture concentrated in vacuo. The resultant gum was dissolved in ether, washed with water, concentrated in vacuo and the residue crystallized first from petroleum ether and then from ether-methanol. The A -=-3(a)-acetoxy- 11-keto-21 bromopregnene thus recovered in about 50% yield had a melting point of 116 to 117 and upon saponification yielded A17'23()- hydroxy-11-keto-21-bromopregnene.

While in the example the starting material used was a compound having the 3-acetoxy group in the trans form, a compound having this group in the cis form also may be used as the steric configuration of the group in the 3 position is not important.

The temperatures mentioned in the example are room temperatures unless otherwise indicated. The temperatures, however, are not critical and the reactions may be carried out at higher or lower temperatures; but extremely high temperatures should be avoided because of the likelihood of decomposition of the desired products which may result from operation at such temperatures. Unless otherwise stated, the reagents can be used in diflerent proportions than are indicated in the above example as the proportions unless otherwise indicated, are not critical, although enough of the reagents should be employed to insure substantially complete reaction to produce the desired products.

All melting points in this specification are corrected.

Since certain changes in carrying out the above process, and certain modifications in the intermediates which embody the invention may be made without departing from the scope of the invention, it is intended that all matter contained in the above description shall be interpreted in an illustrative and not in a limiting sense.

What is claimed is:

1. A compound of the formula:

CHzX

CH; H 

